Bioavailability of AZD0284 and IV Microtracer Study

A Phase I Study To Assess The Absolute Bioavailability Of A Single Oral Dose Of AZD0284 And To Assess The Pharmacokinetics Of A Single Intravenous Microdose Of [14C]AZD0284 In Healthy Subjects.

The Sponsor is developing the study drug, AZD0284, for the potential treatment of Plaque psoriasis. Psoriasis is a skin condition that causes red, flaky, crusty patches of skin covered with silvery scales. It occurs when skin cells are replaced more quickly than usual. The seriousness of psoriasis varies greatly from person to person. For some people it is a minor irritation, but for others it can have a major impact on their quality of life. .

The purpose of the study is to determine how much of AZD0284 is taken up by the body. The safety and tolerability of the drug will also be assessed. It is hoped that the study drug will improve the management of psoriasis.

Study Overview

• Status: Completed
• Conditions: Plaque Psoriasis Vulgaris
• Intervention / Treatment: Drug: AZD0284; Drug: [14C]AZD0284

Detailed Description

The study is a Phase I, single centre, open-label, non-randomized, single dose study performed in 6 healthy male subjects aged 18 to 65 years, inclusive. The study will assess the absolute bioavailability of a single oral dose of AZD0284 and the pharmacokinetics (PK) of a single intravenous (IV) microdose of [14C]AZD0284 in healthy male and female subjects. Oral AZD0284 and [14C] AZD0284 intravenous solution are referred to as the investigational products in this study.

A screening visit to assess the eligibility of the healthy male and female subjects will occur within 28 days of the administration of the investigational product. Screening assessments will include medical history, inclusion/exclusion criteria, demographic data, weight and height, vein assessment, physical examination, blood samples for haematology, clinical chemistry and virology, blood test to confirm post-menopausal status (if female and of non-childbearing potential), blood test to confirm no history of tuberculosis, urine sample for urinalysis, urine test for pregnancy (if female and of childbearing potential) drug screen, alcohol breath test, carbon monoxide (CO) breath test, heart monitoring using ECG, vital signs (blood pressure, heart rate) Study related procedures will only be performed after signing of the Informed Consent Form.

The healthy male and female subjects will be admitted to the study centre the day before administration of the investigational product (Day -1). On Day 1, subjects will be dosed with a single oral dose of 4 to 120 mg AZD0284 oral suspension (Regimen A) followed by 20 μg [14C]AZD0284 solution for IV infusion (Regimen B) beginning 3 hours after the oral dose has been administered. The IV microdose will be infused over 15 minutes and the end of the infusion is expected to be around the predicted tmax of Regimen A.

The subjects will remain in the study centre until the 48 hour post dose PK blood sample is obtained. A follow up visit will occur 5 to 7 days after dosing and will include PK and routine safety assessments.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed and dated, written informed
2. Healthy males or non-pregnant, non-lactating healthy females.
3. Age 18 to 65 years of age.
4. Suitable veins for cannulation or repeated venepuncture.

5. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria:

   • Post-menopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone (FSH) levels in the postmenopausal range.
   • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
6. Body mass index of 18.0 to 30.0 kg/m2, inclusive, or, if outside the range, considered not clinically significant by the investigator, and weigh at least 50 kg and no more than 100 kg, inclusive.
7. Must be willing and able to communicate and participate in the whole study.
8. Must agree to use an adequate method of contraception

Exclusion

1. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the volunteer at risk because of participation in the study, or influence the results of the volunteer's ability to participate in the study.
2. History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).

4. Subject who have increased risk of infection History and/or presence of tuberculosis (TB) positive result for IFN-y release assay (IGRA) (ie QuantiFERON TB-Gold). The test may be repeated if the initial test result is indeterminate.

   Is in a high-risk group for human immunodeficiency virus (HIV) infection within the last 6 months.

   Subjects with a disease history suggesting abnormal immune function in the judgement of the investigator. (This does not include mild allergy such as childhood asthma or eczema).

5. Any clinically significant abnormalities in clinical chemistry, haematology or urinalysis, as judged by the investigator.
6. Any clinically significant abnormal findings in vital signs, as judged by the investigator.
7. Any clinically significant abnormal findings in 12-lead ECG, as judged by the investigator.
8. Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or HIV results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bioavailability of AZD0284; To assess the absolute bioavailability of a single oral dose of AZD0284 in healthy subjects. To assess the pharmacokinetics (PK) of a single intravenous (IV) microdose of [14C]AZD0284 in healthy subjects.	Drug: AZD0284; Subjects will receive a single oral dose of 4 to 120 mg AZD0284 oral suspension 5 mg/mL in the fasted state; Drug: [14C]AZD0284; Following administration of the AZD0284 oral suspension subjects will receive an IV infusion of 20 μg [14C]AZD0284 solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of absolute bioavailability of AZD0284	Absolute bioavailability of AZD0284 will be calculated from area under the plasma concentration versus time curve (AUC) of the oral dose of AZD0284 / AUC of the IV dose of [14C]AZD x IV dose/Oral dose x 100	PK blood samples: pre-dose, post oral dosing at hour, 0.5, 1, 2, 0, 0.5, 1, 2, 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5,3.75, 4, 5, 6, 7, 8, 9, 11, 12, 15, 24, 27, 36, 48 and 72.
Cmax for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0824 in terms of the maximum observed plasma concentration (Cmax) for [14C]AZD0284	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
Tmax for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the the time to maximum observed plasma concentration (Tmax) for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
AUC(0-last) for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the area under the concentration-time curve from dosing to the last measurable concentration for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
AUC(0-inf) for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms the area under the concentration-time curve from dosing extrapolated to infinity for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
AUC%extrap for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the percentage of AUC(0-inf) extrapolated beyond the last measured for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
lambda-z for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the terminal elimination rate constant calculated from the slope of the apparent elimination phase for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
T1/2 for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the apparent terminal elimination half-life for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
CL (total clearance) for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the terminal elimination rate constant calculated from the slope of the apparent elimination phase for [14C]AZD0284	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
Vz for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the volume of distribution at steady state for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
Vss for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the volume of distribution at steady state for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
MRT (mean residence time) for [14C]AZD0284	Pharmacokinetic (PK) profile of the IV dose of AZD0284 in terms of the mean residence time for [14C]AZD0284.	PK blood samples:pre-dose, time relative to oral dosing at hour: 2.83, 2.92, 2.92, 3, 3.08, 3.17, 3.33, 3.5, 3.75, 4, 5, 6, 7, 8, 9, 11, 15, 27, 36, 48 and 72.
Cmax for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0824 in terms of the maximum observed plasma concentration (Cmax) for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
Tmax for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the the time to maximum observed plasma concentration (Tmax) for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
Tlag for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the elapsed time from dosing at which the analyte was first quantifiable in a concentration vs time profile for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
AUC (0-last) for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the area under the concentration-time curve from dosing to the last measurable concentration for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
AUC(0-inf) for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms the area under the concentration-time curve from dosing extrapolated to infinity for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
AUC%extrap for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the percentage of AUC(0-inf) extrapolated beyond the last measured time point for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
lambda-z for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the terminal elimination rate constant calculated from the slope of the apparent elimination phase for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
T1/2 for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the apparent terminal elimination half-life for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.
CL/F for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the apparent total clearance for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 36, 48 and 72.
Vz/F for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms of the apparent volume of distribution for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 , 36, 48 and 72.
MRT for AZD0284	Pharmacokinetic (PK) profile of the oral dose of AZD0284 in terms the mean residence time for AZD0284.	PK blood samples: pre-dose, time relative to oral dosing at hour, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To collect further information about the safety and tolerability of AZD0284 by assessing physical examinations.	Physical examination will be carried out by a fully registered physician at the clinical unit.	Targeted physical examination:screening, pre-dose, time relative to oral dosing at hour 72.
To collect further information about the safety and tolerability of AZD0284 by assessing telemetry	ECGs will be taken in the clinic by a trained research nurse or a trained clinical technician and reviewed by a physician.	Continuous ECG monitoring will commence approximately 10 minutes before dosing commences until 24 hours after the oral dose.
To collect further information about the safety and tolerability of AZD0284 by assessing safety laboratory tests	Collected by a research nurse or trained clinical technician at the clinical unit.	Haematology and clinical chemistry:screening, pre-dose, time relative to oral dosing at hour 24 and 72, virology at screening.
To collect further information about the safety and tolerability of AZD0284 by assessing vital signs	Vital signs will be measured using manual and automated devices by trained staff at the clinical unit.	Blood pressure and pulse rate: screening, pre-dose, post oral dosing at hour 1, 2, 3, 4, 6, 8, 12, 24 and 72.
To collect further information about the safety and tolerability of AZD0284 by assessing 12 Lead Electrocardiogram (ECG)	ECGs will be taken in the clinic by a trained research nurse or a trained clinical technician and reviewed by a physician.	ECGs: screening, pre-dose, post oral dosing at hour, 1, 2, 3, 4, 6, 8, 12, 24 and follow up.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Philip Evans, MBChB, MRCS, Quotient Clinical Ltd, United Kingdom

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2017
• Primary Completion (Actual): March 23, 2017
• Study Completion (Actual): March 23, 2017

Study Registration Dates

• First Submitted: January 20, 2017
• First Submitted That Met QC Criteria: January 20, 2017
• First Posted (Estimate): January 24, 2017

Study Record Updates

• Last Update Posted (Actual): April 13, 2017
• Last Update Submitted That Met QC Criteria: April 12, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Skin Diseases, Papulosquamous; Psoriasis
• Other Study ID Numbers: D7800C00002; 2016-004260-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No